Department of Biology and Biochemistry, University of Houston, Houston, TX, USA Division of Nephrology, Baylor College of Medicine, Houston, TX, USA.
Nephrol Dial Transplant. 2015 Oct;30(10):1630-8. doi: 10.1093/ndt/gfv028. Epub 2015 Mar 31.
l-Glutamate (l-Glu) plays an essential role in the central nervous system (CNS) as an excitatory neurotransmitter, and exerts its effects by acting on a large number of ionotropic and metabotropic receptors. These receptors are also expressed in several peripheral tissues, including the kidney. This review summarizes the general properties of ionotropic and metabotropic l-Glu receptors, focusing on N-methyl-d-aspartate (NMDA) and Group 1 metabotropic glutamate receptors (mGluRs). NMDA receptors are expressed in the renal cortex and medulla, and appear to play a role in the regulation of renal blood flow, glomerular filtration, proximal tubule reabsorption and urine concentration within medullary collecting ducts. Sustained activation of NMDA receptors induces Ca(2+) influx and oxidative stress, which can lead to glomerulosclerosis, for example in hyperhomocysteinemia. Group 1 mGluRs are expressed in podocytes and probably in other cell types. Mice in which these receptors are knocked out gradually develop albuminuria and glomerulosclerosis. Several endogenous agonists of l-Glu receptors, which include sulfur-containing amino acids derived from l-homocysteine, and quinolinic acid (QA), as well as the co-agonists glycine and d-serine, are present in the circulation at concentrations capable of robustly activating ionotropic and metabotropic l-Glu receptors. These endogenous agonists may also be secreted from renal parenchymal cells, or from cells that have migrated into the kidney, by exocytosis or by transporters such as system x(-)(c), or by transporters involved in ammonia secretion. l-Glu receptors may be useful targets for drug therapy, and many selective orally-active compounds exist for investigation of these receptors as potential drug targets for various kidney diseases.
谷氨酸 (l-Glu) 作为一种兴奋性神经递质，在中枢神经系统 (CNS) 中发挥着重要作用，通过作用于大量离子型和代谢型受体发挥作用。这些受体也在包括肾脏在内的许多外周组织中表达。本文综述了离子型和代谢型 l-Glu 受体的一般特性，重点介绍 N-甲基-d-天冬氨酸 (NMDA) 和组 1 代谢型谷氨酸受体 (mGluRs)。NMDA 受体在肾脏皮质和髓质表达，似乎在调节肾血流量、肾小球滤过、近端肾小管重吸收和髓质集合管中的尿液浓缩方面发挥作用。NMDA 受体的持续激活诱导 Ca(2+) 内流和氧化应激，可导致肾小球硬化，例如在高同型半胱氨酸血症中。组 1 mGluRs 在足细胞中表达，可能在其他细胞类型中也有表达。这些受体被敲除的小鼠逐渐出现蛋白尿和肾小球硬化。一些 l-Glu 受体的内源性激动剂，包括来自 l-同型半胱氨酸的含硫氨基酸和喹啉酸 (QA)，以及共激动剂甘氨酸和 d-丝氨酸，以能够强烈激活离子型和代谢型 l-Glu 受体的浓度存在于循环中。这些内源性激动剂也可能通过胞吐作用或通过系统 x(-)(c)等转运体或参与氨分泌的转运体从肾实质细胞或迁移到肾脏的细胞中分泌。l-Glu 受体可能是药物治疗的有用靶点，并且存在许多选择性口服活性化合物，用于研究这些受体作为各种肾脏疾病的潜在药物靶点。
